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Biomedical subjects

A Renieri

Publications and source records attributed to A Renieri.

At least 37 records · Page 2Linked to original sources
PubMed2001

MECP2 gene mutation analysis in the British and Italian Rett Syndrome patients: hot spot map of the most recurrent mutations and bioinformatic analysis of a new MECP2 conserved region.

Rett syndrome (RTT) is an X-linked dominant neurological disorder, which appears to be the most common genetic cause of profound combined intellectual and physical disability in Caucasian females. This syndrome has been associated with mutations of the MECP2 gene, a transcriptional repressor of unknown target genes. We report a detailed mutational analysis of a large cohort of RTT patients from the UK and Italy. This study has permitted us to produce a hot spot map of the mutations identified. Bioinformatic analysis of the mutations, taking advantage of structural and evolutionary data, leads us to postulate the existence of a new functional domain in the MeCP2 protein, conserved among brain-specific regulatory factors.

Adolescent↗
PubMed2001

PAX6 mutation in a family with aniridia, congenital ptosis, and mental retardation.

Congenital aniridia is due to deletions and point mutations in the PAX6 gene. We describe here a case of a mother and her two sons with a syndrome comprising congenital aniridia, ptosis, and slight mental retardation. The sons also show behavioral changes. The possibility of deletion around the PAX6 locus was excluded by polymorphism studies and fluorescence in situ hybridization analysis. Mutation screening of the PAX6 gene revealed the presence of a transversion C719A, resulting in the substitution of arginine for serine at residue 119. We suggest that this missense mutation is responsible both for aniridia and ptosis, and possibly also for the observed cognitive dysfunction in this family.

Abnormalities, Multiple↗
PubMed2001

Multiple endocrine neoplasia type 2 syndromes may be associated with renal malformations.

OBJECTIVE: The RET proto-oncogene is known to be the susceptibility gene for various disease phenotypes, including multiple endocrine neoplasia type 2 (MEN 2). Recent studies have also suggested an involvement of RET in the development of the mammalian kidney. Although kidney agenesis or dysgenesis has been observed in mice lacking functional ret, no clinically relevant kidney abnormalities have been reported in individuals with known RET mutations and familial medullary thyroid carcinoma (FMTC). We have studied a family with five members affected with isolated FMTC. DNA analysis was performed and the involved RET mutation was identified. Amongst these patients were a woman and her son. DESIGN: Case report. SETTING: University department. PATIENTS: A 32-year-old woman and her son with FMTC and unilateral renal agenesis. RESULTS: The woman's abdominal ultrasound findings demonstrated unilateral renal absence of the left kidney. Her son, when only a few months old, had undergone surgical treatment for Hirschsprung's disease. Abdominal ultrasonography was performed recently, and left-side renal absence was diagnosed. Intravenous pyelography confirmed the agenesis of his left kidney, whilst the contralateral kidney displayed compensatory hypertrophy. CONCLUSIONS: The involvement of the RET proto-oncogene in the early growth and differentiation of the human kidney is now generally accepted. We believe that at least a proportion of patients with MEN 2 may have undiagnosed renal malformations. We suggest therefore that noninvasive imaging techniques, such as ultrasonography, should be used to explore the presence of renal abnormalities in subjects with demonstrated RET mutations.

Adult↗
PubMed2000

A mutation in the rett syndrome gene, MECP2, causes X-linked mental retardation and progressive spasticity in males.

Heterozygous mutations in the X-linked MECP2 gene cause Rett syndrome, a severe neurodevelopmental disorder of young females. Only one male presenting an MECP2 mutation has been reported; he survived only to age 1 year, suggesting that mutations in MECP2 are male lethal. Here we report a three-generation family in which two affected males showed severe mental retardation and progressive spasticity, previously mapped in Xq27.2-qter. Two obligate carrier females showed either normal or borderline intelligence, simulating an X-linked recessive trait. The two males and the two obligate carrier females presented a mutation in the MECP2 gene, demonstrating that, in males, MECP2 can be responsible for severe mental retardation associated with neurological disorders.

Adult↗
PubMed2000

Dot-and-fleck retinopathy in Alport syndrome caused by a novel mutation in the COL4A5 gene.

PURPOSE: To describe an unusual form of dot-and-fleck retinopathy in a slower progressive form of X-linked Alport syndrome, caused by a novel missense mutation in the COL4A5 gene. METHOD: Ophthalmic examination, polymerase chain reaction, and single-strand conformational polymorphism analysis of genomic DNA were performed in the proband. RESULTS: Ophthalmoscopy revealed classic dot-and-fleck retinopathy but located in an unusual site. A novel COL4A5 gene mutation changing glycine to cysteine at 177 was identified. CONCLUSIONS: Although there is no correlation between mutation site and the resulting phenotype in Alport syndrome, our findings suggest that further novel mutations and different ocular manifestations may be associated with Alport syndrome.

Adult↗
PubMed2000

Preserved speech variant is allelic of classic Rett syndrome.

Rett syndrome is a neurological disorder affecting predominantly females with regression loss of speech and purposeful hand use, after a few months of almost normal development. Postnatal microcephaly, hand dispraxia, stereotypic 'hand-washing' activities, ataxia, and abnormal breathing are among its most characteristic features. Another aspect of this disorder is growth failure. The preserved speech variant (PSV) shares with Rett syndrome the same course and the stereotypic hand-washing activities but it differs in that patients typically recover some degree of speech and hand use and usually do not show growth failure. Progressive scoliosis, epilepsy and other minor handicaps, usually present in Rett syndrome, are rare in the preserved speech variant. Here we explore the spectrum of mutations affecting the MECP2 gene in a group of 25 classic Rett syndrome girls and in three patients with the preserved speech variant. Among the Rett syndrome group, two novel mutational hot spots (R270X and R294X), four novel mutations, two novel small deletions, as well as the previously reported 806delG, R168X and R255X mutations, were identified in 20/25 patients. Of note, among the preserved speech variants, two patients carry deletions of 41 bp and 44 bp each, which are strikingly similar to those observed in classic Rett syndrome. Our results confirm the presence of mutational hot spots in MECP2, broaden the spectrum of mutations, pinpoint additional mutational hot spots and establish that the preserved speech variant is indeed allelic of the classic form. Phenotype variability is only partially dependent on the kind of MECP2 mutation and other mechanisms such as skewed X-inactivation, and/or modifier gene effects should be investigated to explain the variable recovery in speech and hand use.

Adolescent↗
PubMed2000

Identification and characterization of mouse orthologs of the AMMECR1 and FACL4 genes deleted in AMME syndrome: orthology of Xq22.3 and MmuXF1-F3.

The contiguous gene deletion syndrome AMME is characterized by Alport syndrome, midface hypoplasia, mental retardation and elliptocytosis and is caused by a deletion in Xq22.3, comprising several genes including COL4A5, FACL4 and AMMECR1. We have now cloned the murine Facl4 and Ammecr1 genes and have mapped both novel murine genes to mouse chromosome X band F1-F3. The murine and human orthologs show 96.5% (FACL4) and 95.2% (AMMECR1) identity at the amino acid level, with conservation of the respective putative subcellular localization signals. Our results show that Facl4 and Ammecr1 are the true murine orthologs of the human genes. Furthermore, the mapping of Facl4 and Ammecr1 to MmuXF1-F3 suggests that this subinterval is orthologous, at least for a portion of Xq22. 3.

Amino Acid Sequence↗
PubMed2000

[Molecular genetics and bone diseases].

The authors describe the molecular mechanisms determining some skeletal diseases, in particular those due to a well-defined, single genic defect. In fact, they examine the hereditary disorders due to mutations in the genes encoding the different collagen types and the hereditary diseases secondary to the defects in: a) the structural proteins of cartilage; b) the enzymes and the sulfate transporters of proteoglycans; c) the transcription factors; d) the growth factors. At the end, the authors emphasize the importance of the genetic studies on animal models, for understanding the etiopathogenesis of many human hereditary disorders.

Bone Density↗
PubMed1999

KCNE1-like gene is deleted in AMME contiguous gene syndrome: identification and characterization of the human and mouse homologs.

We describe the identification and characterization of a new gene deleted in the AMME contiguous gene syndrome. This gene is predominantly expressed in heart, skeletal muscle, spinal cord, and brain. Screening of placenta and NT2 cDNA libraries enabled us to obtain the 1.5-kb full-length transcript, which shows a 426-bp open reading frame. Since the resulting 142-amino-acid peptide has a single putative transmembrane domain and a weak but suggestive homology with KCNE1 (minK), a protein associated with the KCNQ1 potassium channel (KVLQT1), we named this new gene KCNE1-like (KCNE1L). To obtain greater insight into this new member of an apparently distinct protein family, we have identified and characterized the homologous mouse gene (Kcne1l), which encodes a peptide of 143 amino acids with 91% homology and 80% identity. The expression pattern of mouse Kcne1l in the developing embryo revealed strong signal in ganglia, in the migrating neural crest cells of cranial nerves, in the somites, and in the myoepicardial layer of the heart. The specific distribution in adult tissues, the putative channel function, and the expression pp6tern in the developing mouse embryo suggest that KCNE1L could be involved in the development of the cardiac abnormalities as well as of some neurological signs observed in patients with AMME contiguous gene syndrome.

Animals↗
PubMed1999

Identification and characterization of a highly conserved protein absent in the Alport syndrome (A), mental retardation (M), midface hypoplasia (M), and elliptocytosis (E) contiguous gene deletion syndrome (AMME).

We recently described a novel contiguous gene deletion syndrome (AMME) in Xq22.3 that includes Alport syndrome (A), mental retardation (M), midface hypoplasia (M), and elliptocytosis (E). While the Alport syndrome is due to deletion of the COL4A5 gene, no other genes are known in the region with the exception of our recent finding of the FACL4 gene. In our effort to isolate additional genes from the deleted region, we have identified the gene named AMMECR1 (Alport syndrome, mental retardation, midface hypoplasia, and elliptocytosis chromosomal region gene 1). RACE experiments and screening of cDNA libraries enabled us to obtain the entire ORF of the gene (1002 bp) followed by about 2 kb of 3'UTR. AMMECR1 is composed of six exons, shows a ubiquitous 6.5-kb transcript, and codes for a protein with a molecular mass of 35.5 kDa. Sequence analysis revealed that this gene is conserved in several species ranging from Caenorhabditis elegans and yeast to micro-organisms. Exon 2 of AMMECR1 encodes a domain consisting of six amino acids identically conserved throughout the course of evolution and whose function is as yet unknown. Analysis of the predicted protein product using ExPAsy tools raises the possibility that the gene may code for a regulatory factor potentially involved in the development of AMME contiguous gene deletion syndrome.

Amino Acid Sequence↗
PubMed1999

Inheritance of a 38-kb fragment in apparently sporadic facioscapulohumeral muscular dystrophy.

Facioscapulohumeral dystrophy (FSHD) is an autosomal-dominant muscular disorder associated with a short (<35 kb) EcoRI/BlnI fragment resulting from deletion of an integral number of units of a 3.3-kb repeat located at 4q35. In this study, we determined fragment sizes separated by pulsed-field gel electrophoresis in a patient with an apparently sporadic case of FSHD and in his healthy family members. A 38-kb fragment was detected in the proband, in his older brother, and in their father. This finding prompted a clinical reevaluation of the father and brother. A subclinical phenotype restricted to abdominal muscle weakness was detected, and serum creatine kinase values were found to be elevated in both. The proband's brother also showed evidence of an independently occurring subtelomeric rearrangement of 4q35, which normally occurs in about 20% of the population. The identification of a "borderline" 38-kb EcoRI/BlnI fragment in an affected subject and his very mildly affected relatives extends the size range of disease alleles and expands existing data on the variable intrafamilial expressivity of FSHD. This study highlights the importance of a careful molecular and clinical analysis extended to family members of apparently sporadic cases with larger EcoRI/BlnI fragments for accurate diagnosis and appropriate genetic counseling in FSHD.

Adult↗
PubMed1999

Autosomal dominant aplasia cutis congenita: report of a large Italian family and no hint for candidate chromosomal regions.

We studied a three-generation pedigree in which seven individuals were affected by aplasia cutis congenita, a rare disorder characterized by the congenital absence of the epidermis, dermis and subcutaneous tissue of the vertex or occipital region. Accurate clinical and formal genetic analysis suggested that this family was affected by the autosomal dominant form of the disease, a hereditary condition due to mutations of an unknown gene. To define the map position of this locus, we performed linkage analysis on candidate chromosomes (long arm of chromosomes 1 and 12). Negative lod scores were obtained for all markers analysed and linkage with genes located in these chromosomal regions was excluded.

Chromosome Mapping↗
PubMed1999

LINE-1 elements at the sites of molecular rearrangements in Alport syndrome-diffuse leiomyomatosis.

Deletions encompassing the 5' termini of the paired type IV collagen genes COL4A5 and COL4A6 on chromosome Xq22 give rise to Alport syndrome (AS) and associated diffuse leiomyomatosis (DL), a syndrome of disseminated smooth-muscle tumors involving the esophagus, large airways, and female reproductive tract. In this study, we report isolation and characterization of two deletion junctions. The first, in a patient described elsewhere, arose by a nonhomologous recombination event fusing a LINE-1 (L1) repetitive element in intron 1 of COL4A5 to intron 2 of COL4A6, resulting in a 13.4-kb deletion. The second, in a previously undescribed family, arose by unequal homologous recombination between the same L1 and a colinear L1 element in intron 2 of COL4A6, resulting in a>40-kb deletion. L1 elements have contributed to the emergence of this locus as a site of frequent recombinations by diverse mechanisms. These give rise to AS-DL by disruption of type IV collagen and perhaps other as yet unidentified genes, evidenced by deletions as small as 13.4 kb.

Adult↗
PubMed1999

Evidence for genetic heterogeneity in benign familial hematuria.

Benign familial hematuria (BFH: MIM141200) is an autosomal-dominant disease accounting for one-fifth of all hematuria of unknown cause in children. Previous observations suggest that BFH may be allelic to recessive Alport syndrome (AS: MIM 203780) with a mutation in the COL4A3/COL4A4 locus. However, it is not clear whether all cases of BFH are due to heterozygous mutation of COL4A3/COL4A4 genes. We report here the exclusion of linkage between BFH and COL4A3/COL4A4 loci at 2q35-37 in a restricted population from Sicily (Italy). Total lod score is -9.6 at theta 0. Furthermore, in some cases exclusion of linkage is evident even considering single families. We conclude that BFH is genetically heterogeneous.

Adult↗
PubMed1999

Intracellular levels of the LIS1 protein correlate with clinical and neuroradiological findings in patients with classical lissencephaly.

We report on the genotype-phenotype correlation in 7 patients with classical lissencephaly carrying a heterozygous subtle mutation in the LIS1 gene. Six patients, showed a mutation predicted to encode for a truncated protein, and one mutation altered a splicing site, resulting in skipping of exon 4. Western blot analysis performed on the lymphoblastoid cell line of 2 patients bearing truncating mutations indicated that the mutated allele did not produce a detectable amount of the LIS1 protein; whereas the analysis performed on the fibroblasts from the patient with a splice-site mutation was suggestive of partial protein synthesis from the mutated allele. Although clinical and magnetic resonance imaging findings of patients with truncating mutations did not differ from those observed in patients with a heterozygous deletion, the patient bearing the exon-skipping mutation had less severe clinical and brain involvement. Our data suggest that truncating mutations in the LIS1 gene are relatively common among patients with classical lissencephaly not bearing a heterozygous deletion at 17p13.3, and strengthen the relevance of correct intracellular dosage of the LIS1 protein in the neuronal migration process.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗
PubMed1998

FACL4, a new gene encoding long-chain acyl-CoA synthetase 4, is deleted in a family with Alport syndrome, elliptocytosis, and mental retardation.

We observed a family in which two boys were diagnosed with Alport syndrome, elliptocytosis, and mental retardation and carried a large deletion of the Xq22.3-q23 region, encompassing the COL4A5 gene. This suggests the possibility of a new contiguous gene syndrome. In an attempt to characterize the genes contributing to this complex phenotype, we have isolated a gene encoding a new long-chain acyl-CoA synthetase (FACL4 or LACS4) from the region deleted in these patients. Among several ESTs identified by searching the human gene map database maintained at the National Center for Biotechnology Information, using the map position as a query, only one was deleted in the patients. RACE products containing the entire ORF were subsequently generated. Northern blot analysis showed a 5-kb mRNA expressed in several tissues except for liver and lung. Brain shows a longer transcript, possibly reflecting the use of a brain-specific upstream ATG start codon. FACL4 encodes a predicted protein product of 670 amino acids (711 in brain), with a remarkable level of conservation compared to the rat acyl-CoA synthetases ACS4 and brain-specific ACS3 protein sequences. We are investigating the possibility that the absence of this enzyme may play a role in the development of mental retardation or other signs associated with Alport syndrome in the family.

Amino Acid Sequence↗